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In order to detect the two splice variant forms of type-IVB cyclic AMP phosphodiesterase (PDE) activity, DPD (type-IVB1) and PDE-4 (type-IVB2), anti-peptide antisera were generated. One set (‘DPD/PDE-4-common’), generated against a peptide sequence found at the common C-terminus of these two PDEs, detected both PDEs. A second set was PDE-4 specific, being directed against a peptide sequence found within the unique N-terminal region of PDE-4. In brain, DPD was found exclusively in the cytosol and PDE-4 exclusively associated with membranes. Both brain DPD and PDE-4 activities, isolated by immunoprecipitation, were cyclic AMP-specific (KmcyclicAMP: approximately 5 microM for DPD; approximately 4 microM for PDE-4) and were inhibited by low rolipram concentrations (K1rolipram approximately 1 microM for both). Transient expression of DPD in COS-1 cells allowed identification of an approx. 64 kDa species which co-migrated on SDS/PAGE with the immunoreactive species identified in both brain cytosol and membrane fractions using the DPD/PDE-4-common antisera. The subunit size observed for PDE-4 (approx. 64 kDa) in brain membranes was similar to that predicted from the cDNA sequence, but that observed for DPD was approx. 4 kDa greater. Type-IV, rolipram-inhibited PDE activity was found in all brain regions except the pituitary, where it formed between 30 and 70% of the PDE activity in membrane and cytosolic fractions when assayed with 1 microM cyclic AMP, PDE-4 formed 40-50% of the membrane type-IV activity in all brain regions save the midbrain (approx. 20%). DPD distribution was highly restricted to certain regions, providing approx. 35% of the type-IV cytosolic activity in hippocampus and 13-21% in cortex, hypothalamus and striatum with no presence in brain stem, cerebellum, midbrain and pituitary. The combined type-IVB PDE activities of DPD and PDE-4 contributed approx. 10% of the total PDE activity in most brain regions except for the pituitary (zero) and the mid-brain (approx. 3%. The isolated cDNAs for DPD and PDE-4 appear to reflect transcription products which are expressed in vivo in brain. The unique N-terminal domain of PDE-4 is suggested to target this PDE to membranes in brain. Type-IVB PDEs are differentially expressed in various brain regions, indicating that there are tissue-specific controls on both the expression of the gene and the splicing of its products.

Converging evidence from biopsychosocial research in humans and animals demonstrates that chronic sensory stimulation (via excessive screen exposure) affects brain development increasing the risk of cognitive, emotional, and behavioural disorders in adolescents and young adults. Emerging evidence suggests that some of these effects are similar to those seen in adults with symptoms of mild cognitive impairment (MCI) in the early stages of dementia, including impaired concentration, orientation, acquisition of recent memories (anterograde amnesia), recall of past memories (retrograde amnesia), social functioning, and self-care. Excessive screen time is known to alter gray matter and white volumes in the brain, increase the risk of mental disorders, and impair acquisition of memories and learning which are known risk factors for dementia. Chronic sensory overstimulation (i.e., excessive screen time) during brain development increases the risk of accelerated neurodegeneration in adulthood (i.e., amnesia, early onset dementia). This relationship is affected by several mediating/moderating factors (e.g., IQ decline, learning impairments and mental illness). We hypothesize that excessive screen exposure during critical periods of development in Generation Z will lead to mild cognitive impairments in early to middle adulthood resulting in substantially increased rates of early onset dementia in later adulthood. We predict that from 2060 to 2100, the rates of Alzheimer’s disease and related dementias (ADRD) will increase significantly, far above the Centres for Disease Control (CDC) projected estimates of a two-fold increase, to upwards of a four-to-six-fold increase. The CDC estimates are based entirely on factors related to the age, sex, race and ethnicity of individuals born before 1950 who did not have access to mobile digital technology during critical periods of brain development. Compared to previous generations, the average 17–19-year-old spends approximately 6 hours a day on mobile digital devices (MDD) (smartphones, tablets, and laptop computers) whereas individuals born before 1950 at the same age spent zero. Our estimates include the documented effects of excessive screen time on individuals born after 1980, Millennials and Generation Z, who will be the majority of individuals ≥65 years old. An estimated 4-to-6-fold increase in rates of ADRD post-2060 will result in widespread societal and economic distress and the complete collapse of already overburdened healthcare systems in developed countries. Preventative measures must be set in place immediately including investments and interventions in public education, social policy, laws, and healthcare.

In an event-related fMRI study, we examined the cortical networks involved in establishing. reference during language comprehension. We compared BOLD responses to sentences containing referentially ambiguous pronouns (e.g., "Ronald told Frank that he..."), referentially failing pronouns (e.g., "Rose told Emily that he...") or coherent pronouns. Referential ambiguity selectively recruited media[ prefrontal regions, suggesting that readers engaged in problemsolving to select a unique referent from the discourse model. Referential failure elicited activation increases in brain regions associated with mo rp ho -syntactic processing, and, for those readers who took failing pronouns to refer to unmentioned entities, additional regions associated with elaborative inferencing were observed. The networks activated by these two referential problems did not overlap with the network activated by a standard semantic anomaly. Instead, we observed a double dissociation, in that the systems activated by semantic anomaly are deactivated by referential ambiguity, and vice versa. This inverse coupling may reflect the dynamic recruitment of semantic and episodic processing to resolve semantically or referentially problematic situations. More generally, our findings suggest that neurocognitive accounts of language comprehension need to address not just how we parse a sentence and combine individual word meanings, but also how we determine who's who and what's what during language COmprehension. (c) 2007 Elsevier Inc. All rights reserved.

Speech and language-related functions tend to depend on the left hemisphere more than the right in most right-handed (dextral) participants. This relationship is less clear in non-right handed (adextral) people, resulting in surprisingly polarised opinion on whether or not they are as lateralised as right handers. The present analysis investigates this issue by largely ignoring methodological differences between the different neuroscientific approaches to language lateralization, as well as discrepancies in how dextral and adextral participants were recruited or defined. Here we evaluate the tendency for dextrals to be more left hemisphere dominant than adextrals, using random effects meta analyses. In spite of several limitations, including sample size (in the adextrals in particular), missing details on proportions of groups who show directional effects in many experiments, and so on, the different paradigms all point to proportionally increased left hemispheric dominance in the dextrals. These results are analysed in light of the theoretical importance of these subtle differences for understanding the cognitive neuroscience of language, as well as the unusual asymmetry in most adextrals.

SummaryIn recent years, vagal nerve stimulation (VNS) has been proposed as a possible way to improve the control of refractory (partial and generalized) seizures. To date, however, there is no complete understanding of the underlying mechanism for this action nor are there any available guidelines or criteria for the selection of those candidates that might be most suitable for this kind of neuromodulating surgery.This report presents evidence that should be helpful in defining the clinical criteria for using VNS for the treatment of refractory seizures. We report on 17 patients with severe partial refractory epilepsy and polymorphous seizures, who have been operated on previously or who were excluded from epilepsy surgery and for whom, at least, one seizure type has been electrographically recorded. Sixteen of these patients also had falling seizures. Our objective was to identify responders and to correlate the outcome of their seizures with the EEGraphic onset of their seizure. Follow-up ranged from 4 to 9 years.The results of this study indicate a significant reduction of seizures in only four patients and better outcome in patients where the onset of seizure activity occurred in the temporal area. Patients with frontal or frontocentral seizures resulted in the poorest outcomes. In four patients with Lennox–Gastaut syndrome VNS produced no significant reduction of seizures, while falling seizures decreased significantly in three patients with retropulsive falls.These results of this small series of patients suggest that VNS might be more suitable in patients with temporal rather than frontal or central seizure onset. Further studies are required to support this hypothesis.

Робота присвячена аналізу зв’язку між електричною активністю мозку та серцево-судинної системи людини у хворих на епілепсію в період перед початком епілептичного нападу. Запропоновано кількісно оцінювати зв’язок з використанням взаємної інформації між повними потужностями електроенцефалограми та кардіоритмограми в часових вікнах протягом години до початку нападу. Результати клінічних досліджень для десяти сигналів, які містять напади, показали суттєве зниження взаємної інформації за 5 хвилин перед початком нападу. The paper analyzes the relation between the brain and cardiovascular system activity in patients with epilepsy in the period before an epileptic seizure. Quantification of the connection by mutual information between full power of electroencephalogram and cardiorhythmogram in time windows for an hour before the seizure is proposed. Clinical study results for ten signals containing seizures showed a significant reduction of the mutual information in 5 minutes before the seizure. Работа посвящена анализу связи между электрической активностью мозга и сердечно-сосудистой системы у больных эпилепсией в период перед началом эпилептического приступа. Предложено количественно оценивать связь с использованием взаимной информации между полными мощностями электроэцефалограммы и кардиоритмограмы во временных окнах за час до начала приступа. Результаты клинических исследований для десяти сигналов, содержащих приступы, показали существенное снижение взаимной информации за 5 минут перед началом приступа.

The insula is a multimodal sensory integration structure that, in addition to serving as a gateway between somatosensory areas and limbic structures, plays a crucial role in autonomic nervous system function. While anatomical studies following the development of the insula have been conducted, currently, no studies have been published in human fetuses tracking the development of neuronal migration or of white matter tracts in the cortex. In this study, we aimed to follow the neuronal migration and subsequent maturation of axons in and around the insula in human fetal ages. Using high-angular resolution diffusion magnetic resonance imaging tractography, major white matter pathways to/from the insula and its surrounding operculum were identified at a number of time points during human gestation. Pathways likely linked to neuronal migration from the ventricular zone to the inferior frontal gyrus, superior temporal region, and the insular cortex were detected in the earliest gestational age studied (15 GW). Tractography reveals neuronal migration to areas surrounding the insula occurred at different time points. These results, in addition to demonstrating key time points for neuronal migration, suggest that neurons and axonal fiber pathways underlying the insula and its surrounding gyri mature differentially despite their relationship during cortical folding.